Target identification for the diagnosis and intervention of vulnerable atherosclerotic plaques beyond 18F-fluorodeoxyglucose positron emission tomography imaging: promising tracers on the horizon

Abstract

Cardiovascular disease is the major cause of morbidity and mortality in developed countries and atherosclerosis is the major cause of cardiovascular disease. Atherosclerotic lesions obstruct blood flow in the arterial vessel wall and can rupture leading to the formation of occlusive thrombi. Conventional diagnostic tools are still of limited value for identifying the vulnerable arterial plaque and for predicting its risk of rupture and of releasing thromboembolic material. Knowledge of the molecular and biological processes implicated in the process of atherosclerosis will advance the development of imaging probes to differentiate the vulnerable plaque. The development of imaging probes with high sensitivity and specificity in identifying high-risk atherosclerotic vessel wall changes and plaques is crucial for improving knowledge-based decisions and tailored individual interventions. Arterial PET imaging with ¹⁸F-FDG has shown promising results in identifying inflammatory vessel wall changes in numerous studies and clinical trials. However, due to its limited specificity in general and its intense physiological uptake in the left ventricular myocardium that impair imaging of the coronary arteries, different PET tracers for the molecular imaging of atherosclerosis have been evaluated. This review describes biological, chemical and medical expertise supporting a translational approach that will enable the development of new or the evaluation of existing PET tracers for the identification of vulnerable atherosclerotic plaques for better risk prediction and benefit to patients.

Keywords: Atherosclerotic plaque; Cardiovascular disease; PET tracers; Vascular calcification; Vascular smooth muscle cells.

Fig. 1

Fused PET/CT and CT images show ⁶⁸Ga-DOTATATE uptake in the left common carotid artery close to the bifurcation (arrows), which is visually and semiquantitatively higher than in the right carotid artery, indicating increased inflammatory changes in the left carotid artery

Fig. 2

Fused PET/CT images show only slight ⁶⁸Ga-DOTATATE uptake at the bifurcation of the left carotid artery with, on the CT images, as part of the fused PET/CT images, visible calcification (arrow). Combined molecular (⁶⁸Ga-DOTATATE PET) and morphological imaging (CT) indicates more stable, chronic arterial vessel wall changes

Fig. 3

Sprague Dawley rats at 10–12 weeks of age were subjected to either a chow diet or a chow diet supplemented with warfarin (3 mg/g + 1.5 mg/g K1) for 2 weeks. a b ¹⁸F-NaF PET/CT images obtained after 2 weeks in animals on the chow diet (a) and in animals on the warfarin-supplemented chow diet (b): animals on the supplemented diet show uptake in the descending aorta indicating hotspots of calcification which are not seen in the animals on the chow diet. c Ex vivo histochemical Alizerin Red staining of aortic tissue reveals calcification of the vasculature

Fig. 4

Left: Model of chemokine CCL5 synthesized by Boc-based SPPS and NCL. An extra lysine residue was coupled at the C-terminus of CCL5. Subsequently, a bimodal rhodamine/DTPA label was conjugated through an oxime bond. Right: Confocal microscopy imaging of mouse bone marrow derived macrophages (BMMs) and 3T3 fibroblasts. a DIC contrast image of BMMs; b Merged image of BMMs stained with CCL5–rhodamine/DTPA (1,500 nM) and with SYTO13 (2 μM; nuclei staining); c DIC contrast image of 3T3 fibroblasts; d Merged image of 3T3 fibroblasts stained with CCL5–rhodamine/DTPA (1,500 nM) and SYTO13 (2 μM)

Fig. 5

Vitamin K metabolism in the secretion of vitamin K-dependent MGP. Scheme of the vitamin K cycle: in the endoplasmic reticulum, posttranslational modification of Glu to Gla residues via reduction of vitamin K to the hydroquinone form (KH₂). KH₂ is oxidized to KO by the enzyme GGCX thereby facilitating the carboxylation of ucMGP to cMGP. The enzyme VKOR recycles KO back to K and KH₂ so that vitamin K can be used some 1,000 times. VKA inhibits VKOR and thus the recycling of vitamin K. This causes a vitamin K deficiency with subsequent ucMGP formation. UcMGP is inactive thereby allowing the formation of microcalcifications

Fig. 6

Different types of vascular calcification can occur in the vasculature. Vascular calcification is clinically measured by CT and represents the amount of vascular burden. Moreover, calcification detected on CT in the media relates to vascular stiffness. However, microcalcification cannot be visualized by CT and these early stages of calcification can now be detected by ¹⁸F-NaF PET. Microcalcifications are responsible for destabilizing the plaque, causing an increased risk of plaque rupture. They also cause vascular remodelling when present in the vascular media. The measurement of inactive MGP as a marker of increased risk of the formation of microcalcifications is currently under development